Sustained-release preparations for the adjustment of blood concentrations of drugs are highly useful in terms of separation between the main pharmacological effect and adverse reaction, improvement in compliance (e.g., the number of doses reduced by improvement in prolonged efficacy), medical economy, etc. In this regard, some techniques have been reported for sustained-release preparations. Meanwhile, since compounds exhibiting the main pharmacological effect have diverse chemical properties, some techniques, albeit still insufficient, of formulating sustained-release preparations aimed at adapting to the diversity of these compounds have been reported (see e.g., Patent Literatures 1 and 2).
A narcotic analgesic hydromorphone (see e.g., Non-patent Literature 1) has a potent analgesic effect and exhibits an analgesic effect 3.5 times as strong as that of oxycodone and 5 times as strong as that of morphine upon oral administration, and 8 times as strong as that of morphine as injections. In addition, this drug can be administered to patients having difficulties in taking increased doses of existing drugs. For these reasons, the drug is widely used around the world and also used over a long duration. Hydromorphone and another narcotic analgesic oxycodone are known to be highly tolerated, compared with morphine, in terms of opioid-specific adverse reactions (constipation, nausea or vomiting, itching, somnolence, respiratory depression, etc.). Oxycodone is known to undergo metabolism by cytochrome CYP450 (CYP3A4 or CYP2D6) and thus care is required for its combined use with drugs that inhibit CYP3A4 or CYP2D6. On the other hand, hydromorphone inhibits cytochrome CYP450 (CYP3A4 or CYP2D6) less than oxycodone, fentanyl, and morphine and, advantageously, is unlikely to interact with drugs that are metabolized by CYP. In addition, its metabolites have no analgesic effect. Hydromorphone therefore has the following advantages: for example, the drug can be used more safely than morphine even for patients with deteriorated functions of the kidney, which serves as an excretion pathway; the drug exhibits no histamine release action; and the drug has less adverse reaction (itching) than that of morphine.
In cancer treatment, pain management is very important for improving QOL of patients and also makes up a significant portion of the treatment. Hydromorphone or oxycodone is a typical drug used overseas in opioid rotation for cancer pain and probably makes a great contribution as a standard drug to control pain for patients.
In general, a problem in the design of sustained-release preparations for oral administration is dose dumping of the drug when the sustained-release preparation collapses due to mechanical stress resulting from the presence of food in the upper gastrointestinal tract, gastrointestinal motility, and so on (see Patent Literature 3). Hydromorphone or oxycodone is a basic compound and a highly water-soluble drug and is therefore easily soluble in a neutral aqueous solution such as a neutral buffer. Dose dumping of the narcotic analgesic, however, has the risk of becoming a lethal adverse reaction in some cases. A solution to the problem of dose dumping is a crucial issue for sustained-release preparations of the narcotic analgesic. According to study results, Palladone®, a previously known sustained-release preparation of the narcotic analgesic hydromorphone, was found to cause dose dumping resulting from damage to the sustained release preparation, when taken together with an alcohol (see e.g., Non-patent Literature 2). Hence, the U.S. Food and Drug Administration (FDA) requested the withdrawal of sustained-release capsules of Palladone® from the market (see the FDA press release of Jul. 13, 2005). The FDA further warned patients that they may incur deadly consequences by taking Palladone® with an alcohol beverage. Against this background, there has been a demand for an alcohol-resistant sustained-release preparation (sustained-release pharmaceutical composition) containing a narcotic analgesic such as hydromorphone or oxycodone as a principal pharmaceutically active ingredient without possible dose dumping.